The present invention relates to a series of new derivatives of the known compound ML-236B, to processes for their preparation and to pharmaceutical compositions containing them.
ML-236B is disclosed in U.S. Pat. No. 3,983,140 and the term "ML-236B" is used to refer to two compounds, a lactone, termed "ML-236B lactone", which has the structural formula: ##STR2## and the corresponding free hydroxy-carboxylic acid, termed "ML-236B carboxylic acid", which has the structural formula: ##STR3##
These ML-236B compounds have been isolated and purified from the metabolic products of microorganisms of the genus Penicillium, especially Penicillium citrinum, a species of blue mould. They have been shown to inhibit the biosynthesis of cholesterol by enzymes or cultured cells separated from experimental animals by competing with the rate-limiting enzyme active in the biosynthesis of cholesterol, that is to say 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and, as a result, significantly reduce serum cholesterol levels in animals [Journal of Antibiotics, 29, 1346 (1976)].
A number of compounds structurally related to ML-236B have also been discovered and some have been found to share this ability to inhibit the biosynthesis of cholesterol. Of the ML-236B derivatives which have been discovered, the most relevant form the subject of copending U.S. patent application Ser. No. 270,846, filed 5th June 1981 which issued as U.S. Pat. No. 4,346,227. In the lactone form, these compounds may be represented by the structural formula: ##STR4## and have been named IsoM-4 lactone or IsoM-4' lactone, depending upon the particular configuration of the various asymmetric carbon atoms present in the molecule. The corresponding IsoM-4 carboxylic acid and IsoM-4' carboxylic acid are also disclosed and these compounds were all found to have the ability to inhibit the biosynthesis of cholesterol.
The IsoM-4 and IsoM-4' compounds and their alkali metal salts may be prepared by the enzymatic hydroxylation of ML-236B or of a derivative thereof and other salts and the esters may, of course, then be prepared by conventional salification or esterification procedures starting with the resulting hydroxylation product. The enzymatic hydroxylation is preferably effected using a suitable microorganism or an enzyme-containing extract of such a microorganism, although it may also be effected as part of the mammalian metabolism of ML-236B or by using the liver or an enzyme-containing extract from the liver of such an animal. Preferred microorganisms for use in this process include those of the genera Absidia, Cunninghamella, Syncephalastrum,
We have now surprisingly discovered that the treatment of ML-236B lactone or ML-236B carboxylic acid or a salt or alkyl ester thereof with certain of these microorganisms or with enzyme-containing extracts therefrom can also produce other distinct, but related, compounds which likewise have the ability to inhibit the biosynthesis of cholesterol.
Moreover, the new compounds of the invention are metabolized with much greater difficulty after administration than is ML-236B. The compounds of the invention are thus less readily deactivated and hence have more persistent activity, with attendant advantages well recognized in the art.